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1.
Anticancer Res ; 40(1): 35-52, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892551

RESUMO

BACKGROUND/AIM: Co-expression of c-Met and ALDH1A3 indicates a poor prognosis in stage III-IV breast cancers and contributes to cell proliferation and tumor formation by ALDH1-positive breast CSCs. PKCλ is overexpressed and contributes to a poor prognosis in several cancers. MATERIALS AND METHODS: A breast cancer genomics data set (METABRIC, n=2509) was downloaded and analyzed, as was the effect c-Met and PKCλ inhibitors on ALDH1high cell viability and tumor-sphere formation. RESULTS: c-Met expression correlates with expression of PKCλ in breast cancer. Stage III-IV breast cancer patients with c-Methigh PKCλhigh ALDH1A3high have a poorer prognosis than patients with c-Metlow PKCλlow ALDH1A3low Foretinib and auranofin suppressed cell viability and tumor-sphere formation by ALDH1high cells. These results suggest that c-Met and PKCλ are cooperatively involved in cancer progression and contribute to poor prognoses in breast cancer. CONCLUSION: c-Met and PKCλ are potentially useful prognostic markers and therapeutic targets in late-stage breast cancer.


Assuntos
Aldeído Oxirredutases/genética , Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Proteína Quinase C/genética , Proteínas Proto-Oncogênicas c-met/genética , Aldeído Oxirredutases/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo
2.
J Enzyme Inhib Med Chem ; 35(1): 139-144, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31724435

RESUMO

A series of naphthalene-chalcone derivatives (3a-3t) were prepared and evaluated as tubulin polymerisation inhibitor for the treatment of breast cancer. All compounds were evaluated for their antiproliferative activity against MCF-7 cell line. The most of compounds displayed potent antiproliferative activity. Among them, compound 3a displayed the most potent antiproliferative activity with an IC50 value of 1.42 ± 0.15 µM, as compared to cisplatin (IC50 = 15.24 ± 1.27 µM). Additionally, the promising compound 3a demonstrated relatively lower cytotoxicity on normal cell line (HEK293) compared to tumour cell line. Furthermore, compound 3a was found to induce significant cell cycle arrest at the G2/M phase and cell apoptosis. Compound 3a displayed potent tubulin polymerisation inhibitory activity with an IC50 value of 8.4 µM, which was slightly more active than the reference compound colchicine (IC50 = 10.6 µM). Molecular docking analysis suggested that 3a interact and bind at the colchicine binding site of the tubulin.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Chalconas/farmacologia , Naftalenos/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalconas/química , Colchicina/antagonistas & inibidores , Colchicina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Naftalenos/química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
3.
J Enzyme Inhib Med Chem ; 35(1): 172-186, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31752564

RESUMO

Sphingosine kinase 1 (SphK1) is a promising therapeutic target against several diseases including mammary cancer. The aim of present work is to identify a potent lead compound against breast cancer using ligand-based virtual screening, molecular docking, MD simulations, and the MMPBSA calculations. The LBVS in molecular and virtual libraries yielded 20,800 hits, which were reduced to 621 by several parameters of drug-likeness, lead-likeness, and PAINS. Furthermore, 55 compounds were selected by ADMET descriptors carried forward for molecular interaction studies with SphK1. The binding energy (ΔG) of three screened compounds namely ZINC06823429 (-11.36 kcal/mol), ZINC95421501 (-11.29 kcal/mol), and ZINC95421070 (-11.26 kcal/mol) exhibited stronger than standard drug PF-543 (-9.9 kcal/mol). Finally, it was observed that the ZINC06823429 binds tightly to catalytic site of SphK1 and remain stable during MD simulations. This study provides a significant understanding of SphK1 inhibitors that can be used in the development of potential therapeutics against breast cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Relação Estrutura-Atividade
4.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(9): 828-831, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31750826

RESUMO

Objective To investigate the correlations between the expression of vascular endothelial growth factor (VEGF) and thrombospondin 1 (TSP-1) in breast cancer and the prognosis. Methods Immunohistochemical staining was used to detect the expression of VEGF and TSP-1 in 160 cases of breast cancer tissues and adjacent tissues, and the relationships between them were analyzed. Results The expression of TSP-1 significantly decreased and the expression of VEGF significantly increased in breast cancer tissues. Low expression of TSP-1 and high expression of VEGF were significantly associated with high clinical stage, poor differentiation, and lymph node metastasis. After 3 years of follow-up, the recurrence rate was 15.6%. Spearman rank correlation analysis showed that there was a positive correlation between the prognosis recurrence rate and the positive expression rate of VEGF (r=0.459), but negatively correlated with the positive expression rate of TSP-1 (r=-0.543). Logistic regression analysis showed that TSP-1 positive expression rate, VEGF positive expression rate, lymph node metastasis and clinical stage were the main independent risk factors for prognosis and recurrence. Conclusion The high expression of VEGF and the low expression of TSP-1 in breast cancer tissues are significantly correlated with the main clinical features. The recurrence rate of patients with high expression of VEGF and low expression of TSP is high.


Assuntos
Neoplasias da Mama/diagnóstico , Trombospondina 1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neoplasias da Mama/metabolismo , Feminino , Humanos , Recidiva Local de Neoplasia , Prognóstico
5.
Anticancer Res ; 39(11): 5879-5890, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704812

RESUMO

BACKGROUND/AIM: The aim of the study was to investigate the prognostic role of androgen receptor (AR), mineralocorticoid receptor (MR) and glucocorticoid receptor ß (GRß) expression in HER-2 negative breast cancer patients. MATERIALS AND METHODS: The study population (n=152) was enriched with triple-negative breast cancers (TNBC) (n=96; 63.2%). The median follow-up time was 100 months. AR, MR and GRß immunocytochemical staining was compared with that of epithelial-mesenchymal transition (EMT) markers (vimentin, SIP1, ZEB1). RESULTS: High expression of cytoplasmic MR was associated with dismal local relapse-free survival (RR=13.923; 95%CI=1.071-181.045; p=0.044) in tumours with non-TNBC phenotype. AR and GRß were more frequently expressed in ER+/PR+/HER2- tumours, while cytoplasmic MR was more often expressed in TNBC tumours (for all, p<0.0005). GRß and AR were associated with decreased vimentin expression (p<0.005), indicating their association with attenuated EMT. CONCLUSION: Cytoplasmic MR expression is a strong predictor of local recurrence in non-metastatic breast cancer patients with non-TNBC tumour phenotype.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/classificação , Neoplasias da Mama/mortalidade , Citoplasma/metabolismo , Recidiva Local de Neoplasia/mortalidade , Receptores de Mineralocorticoides/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Metástase Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Androgênicos/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida
6.
Zhongguo Zhong Yao Za Zhi ; 44(17): 3786-3791, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31602954

RESUMO

It is reported that energy metabolism is the core feature of tumor cells. This study is aimed to investigate the regulatory effect of two flavonoids( glabridin and quercetin) on energy supply and glycolysis of breast cancer cells,and provide reference for developing some anticancer herbal drugs with the function of regulating tumor energy metabolism. Based on the characteristics of each pathway during energy metabolism,in the present study,the triple negative breast cancer tumor cells( MDA-MB-231) were selected to investigate the effects of glabridin and quercetin on the energy metabolism of breast cancer cells and discuss the possible mechanisms from the following five potential targets: glucose uptake,protein expression of glucose transporter 1( GLUT1),adenosine triphosphate( ATP) level,lactate dehydrogenase( LDH) activity,and lactic acid( LD) concentration. The results showed that both quercetin and glabridin could decrease the glucose uptake capacity of breast cancer cells by down-regulating the protein expression of GLUT1. Quercetin had no significant effect on LDH activity and LD concentration; it did not affect the glycolysis process,but increased the intracellular ATP level. Glabridin decreased the activity of LDH and reduced LD concentration,thereby inhibiting the glycolysis metabolism of breast cancer cells. Therefore,both quercetin and glabridin can regulate the energy metabolism of breast cancer cells and can be used as potential anticancer agents or anti-cancer adjuvants.


Assuntos
Neoplasias da Mama/metabolismo , Metabolismo Energético , Isoflavonas/farmacologia , Fenóis/farmacologia , Quercetina/farmacologia , Linhagem Celular Tumoral , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Humanos
7.
Life Sci ; 237: 116945, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31605710

RESUMO

AIM: Over-expression of histone deacetylase 8 (HDAC8) has been demonstrated in breast cancer. But the underlying molecular mechanism of HDAC8 on the progression of breast cancer remains unknown. MicroRNAs (miRs) are proposed as important molecules in cancer progression by targeting specific oncogenes or tumor-suppressor genes. Our overall objective was to assess the miR-216b-5p role on HDAC8; and its impacts on breast cancer (BC) progression. MAIN METHODS: We acquired cancerous and noncancerous tissues from Iran Tumor Bank (I.T.B). The MDA-MB-231, MCF-7 and MCF-10A BC cell lines were also purchased. The tissue and cell line expression levels of miR-216b-5p and HDAC8 were determined by quantitative real-time PCR (qPCR). We next measured protein levels of HDAC8 by Western blotting assay. The cell cycle, cell proliferation, and colony formation assay were determined. Finally, we investigated the role of HDAC8 using a knockout vector; and confirmed the targeting of 3' untranslated region (3'-UTR) of HDAC8 through miR-216b-5p using a luciferase reporter assay. KEY FINDINGS: Our results demonstrated a significant decrease in miR-216b-5p, and remarkable increase in HDAC8 levels within human breast cancer tissues and cell lines. The lower levels of miR-216b-5p were negatively correlated with lymph node metastasis and advanced tumor size. The overexpression of miR-216b-5p in BC cell lines inhibited cellular proliferation and progression. HDAC8 was directly down-regulated by miR-216b-5p and knockout of HDAC8 showed the similar effects as miR-216b-5p overexpression. SIGNIFICANCE: Briefly, HDAC8 is an oncogene that accelerate breast cancer proliferation and progression and miR-216b-5p modulates those functions by binding to HDAC8 3'-UTR.


Assuntos
Neoplasias da Mama/patologia , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/metabolismo , MicroRNAs/genética , Proteínas Repressoras/metabolismo , Apoptose , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Ciclo Celular , Regulação para Baixo , Feminino , Histona Desacetilases/genética , Humanos , Prognóstico , Proteínas Repressoras/genética , Células Tumorais Cultivadas
8.
Br J Radiol ; 92(1104): 20190425, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31593482

RESUMO

OBJECTIVE: Overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancers provides promising opportunities for imaging and targeted therapy. Developing HER2 targeted positron emission tomography (PET) probes might be benefit for management of the disease. Small high-affinity scaffold proteins, affibodies, are ideal vectors for imaging HER2 overexpressed tumors. Despite of the initial success on development of 18F labeled ZHER2:342 affibody, the tedious synthesis producers, low yields and unfavorable pharmacokinetics may hinder the clinical use. 68Ga is an attractive positron emitter for PET imaging. A simple preparation of 68Ga labeled ZHER2:342 analog, 68Ga-NOTA-MAL-Cys-MZHER2:342, was reported in the study. The in vivo performances of the tracer for assessing HER2 status in breast cancers were also evaluated. METHODS: NOTA-MAL conjugated Cys-MZHER2:342 was radiolabeled with 68Ga. The probe was evaluated by in vitro tests including stability and cell binding studies in breast cancer cells with different HER2 levels. In vivo evaluation was performed in mice bearing tumors using microPET imaging and biodistribution experiments. A PET/CT imaging study was initially performed in patients with breast cancers. RESULTS: The tracer was synthesized in a straightforward chelation method with satisfactory non-decay corrected yield (81±5%) and radiochemical purity (>95%). In vivo micro-PET imaging showed that HER2 high levels expressed BT474 xenografts were more clear visualized than HER2 low levels expressed MCF-7 tumors (16.12 ± 2.69 ID%/g vs 1.32 ± 0.19 ID%/g at 1 h post-injection). The outcome was consistent with the immunohistochemical analysis. No significant radioactivity was accumulated in healthy tissues (less than 2% ID/g) except kidneys. In a preliminary clinical study, 68Ga-NOTA-MAL-Cys-MZHER2:342 PET imaging allowed more high-contrast detection of HER2 positive primary tumors (maximum standardized uptake value = 2.16±0.27) than those in HER2 negative primary focus (maximum standardized uptake value = 0.32±0.05). No detectable side-effects were found. CONCLUSION: In summary, this study indicates the significant efficiency of the 68Ga labeled HER2 affibody. Preclinical and clinical studies support the possibility of monitoring HER2 levels in breast cancers using 68Ga-NOTA-MAL-Cys-MZHER2:342. ADVANCES IN KNOWLEDGE: The research investigated the feasibility of a 68Ga labeled HER2 affibody modified with a hydrophilic linker for breast cancer PET imaging. Favorable outcomes showed that the probe might be valuable for determining HER2 status of the disease.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Radioisótopos de Gálio/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Receptor ErbB-2/metabolismo , Proteínas Recombinantes de Fusão/farmacocinética , Animais , Neoplasias da Mama/patologia , Cromatografia Líquida de Alta Pressão , Estudos de Viabilidade , Feminino , Xenoenxertos , Humanos , Rim/diagnóstico por imagem , Rim/metabolismo , Células MCF-7 , Camundongos , Camundongos Nus , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Proteínas Recombinantes de Fusão/síntese química , Distribuição Tecidual
9.
Medicine (Baltimore) ; 98(38): e17262, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31568001

RESUMO

BACKGROUND: This study will systematically investigate the efficacy and safety of the combination of pertuzumab, trastuzumab, and docetaxel (PTD) for treatment of patients with HER2-positive breast cancer (HER2-PBC). METHODS: A comprehensive literature search for this study will consist of 2 parts: electronic database records and gray literature. The electronic database literatures are searched from PubMed, EMBASE, Cochrane Library, Web of Science, Google Scholar, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. All databases will be searched from inception up to the present. In addition, gray literatures, such as dissertations, ongoing trials, and so on, will also be searched. Two authors will independently read the records, extract data collection, and evaluate the risk of bias. RevMan V.5.3 software will be applied for statistical analysis. RESULTS: This study will summarize up-to-date evidence of PTD for patients with HER2-PBC via overall survival, complete response, cancer-specific survival, recurrence-free survival, disease-free survival, quality of life, and toxicities. CONCLUSION: This study will provide efficacy and safety of PTD for HER2-PBC.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Docetaxel/uso terapêutico , Genes erbB-2 , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Docetaxel/administração & dosagem , Feminino , Humanos , Trastuzumab/administração & dosagem , Resultado do Tratamento
10.
Medicine (Baltimore) ; 98(43): e17659, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651890

RESUMO

RATIONALE: It is largely unknown about the tumor growth of breast cancer naturally. We devised and analyzed an appropriate mathematical tool of the equations that describe how fast tumors grow without treatment on the basis of the ellipsoid shape of solid breast cancer. PATIENT CONCERNS: A 31-year-old woman presented with a painless palpable lump in her left breast for 5 months. DIAGNOSIS: Infiltrated ductal breast cancer (histologic grade II) of luminal B INTERVENTIONS:: The patient did not receive any therapy due to her private reasons for 2 years, the analysis of the tumor volume growth was done regarding the growth rate of the tumor in the absence of intervention. OUTCOMES: After 2 years of diagnosis of breast cancer, the tumor mass occupied the whole left breast with skin implanted and nipple abnormality. As this case indicated that the tumor's early growth rate was very slow. When the tumor volume reached 300 cm, its fast growth began without treatment. Later growth approached the maximum, when the tumor volume was more than 800 cm. LESSONS: The tumor growth is segmental without therapy. Early diagnosis and treatment is the key to good prognosis for every breast cancer patient.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Receptor ErbB-2/metabolismo , Adulto , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Feminino , Humanos , Gradação de Tumores , Carga Tumoral
11.
Braz J Med Biol Res ; 52(11): e8657, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31664305

RESUMO

Although Taxol has improved the survival of cancer patients as a first-line chemotherapeutic agent, an increasing number of patients develop resistance to Taxol after prolonged treatment. The potential mechanisms of cancer cell resistance to Taxol are not completely clear. It has been reported that microRNAs (miRNAs) are involved in regulating the sensitivity of cancer cells to various chemotherapeutic agents. In this study, we aimed to explore the role of miR-129-5p in regulating the sensitivity of breast cancer cells to Taxol. Cell apoptosis and autophagy, and the sensitivity of MCF-7 cells to Taxol were assessed with a series of in vitro assays. Our results showed that the inhibition of autophagy increased the Taxol-induced apoptosis and the sensitivity of MCF-7 cells to Taxol. Up-regulation of miR-129-5p also inhibited autophagy and induced apoptosis. Furthermore, miR-129-5p overexpression increased the sensitivity of MCF-7 cells to Taxol. High mobility group box 1 (HMGB1), a target gene of miR-129-5p and a regulator of autophagy, was negatively regulated by miR-129-5p. We found that interference of HMGB1 enhanced the chemosensitivity of Taxol by inhibiting autophagy and inducing apoptosis in MCF-7 cells. Taken together, our findings suggested that miR-129-5p increased the chemosensitivity of MCF-7 cells to Taxol through suppressing autophagy and enhancing apoptosis by inhibiting HMGB1. Using miR-129-5p/HMGB1/autophagy-based therapeutic strategies may be a potential treatment for overcoming Taxol resistance in breast cancer.


Assuntos
Antineoplásicos Fitogênicos/metabolismo , Neoplasias da Mama/metabolismo , Proteína HMGB1/metabolismo , Células MCF-7/metabolismo , MicroRNAs/metabolismo , Paclitaxel/metabolismo , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/genética , Autofagia/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Proteína HMGB1/genética , Humanos , MicroRNAs/genética , Paclitaxel/uso terapêutico , Regulação para Cima/genética
12.
J Cancer Res Clin Oncol ; 145(12): 2983-2994, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31628534

RESUMO

PURPOSE: Accurate monitoring of predictive markers is of utmost importance as oncological treatment decisions almost entirely depend on these factors. In this study, we conducted a quality control assessment on hormone receptors, Her2 status, Ki67 Labelling Index (LI) and histological grading in breast cancer over 4 years (2015-2018). METHODS: Altogether 2214 consecutive breast cancer cases were included. Data on estrogen (ER) and progesterone receptors (PR), Her2 and Ki67, were available in all cases and were tested mostly on preoperative biopsies, in selected cases on postoperative surgical specimens. ER, PR, and Ki67 were assessed with immunohistochemistry (IHC), Her2 status with IHC and fluorescence in situ hybridization. RESULTS: ER/PR were positive in 74-79% cases, ER/PR/Her2 negative in 6.16-10.70% and Her2 positive in 11.49-13.88%/year. Ki67 had median values as 15-17.5% in ER/PR-positive cases, 55-60% in triple-negative cases and 30-32.50% in Her2-positive cases. Histological grading distribution for well (G1), moderately (G2) and poorly (G3) differentiated carcinomas was 15.8-19.1% for G1, 54.2-54.8% for G2 and 21.7-23.7% for G3 cases. Variation in yearly distributions was not significant in any of these markers. CONCLUSIONS: Predictive markers displayed a yearly similar distribution in breast cancer cases independently of grading or of intrinsic subtypes. These results point to a qualitative high performance of predictive marker assessment in breast cancer, corresponding to expected on average positivity rate per marker and per year. It is recommended to monitor positivity rate of ER, PR, Ki67 and Her2 yearly or periodically to comply with quality assurance requirements.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Antígeno Ki-67/metabolismo , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Feminino , Humanos
13.
Chem Commun (Camb) ; 55(90): 13542-13545, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31647067
14.
Zhonghua Zhong Liu Za Zhi ; 41(9): 681-685, 2019 Sep 23.
Artigo em Chinês | MEDLINE | ID: mdl-31550858

RESUMO

Objective: To investigate the expression discordances of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor2 (HER-2) and Ki-67 in primary and metastatic breast cancer specimens and explore the clinical significances. Methods: Biopsies of metastatic lesions were performed in 203 patients with breast cancer recurrence and metastasis indicated by physical examination and/or imaging examination. We confirmed pathological properties and assessed the expressions of ER, PR, HER-2 and Ki-67 in primary and metastatic lesions, their relationships with prognosis were also analyzed. Results: Biopsy failed in 3 patients, the pathology and immunohistochemitry results of metastatic lesions were not obtained. One person was diagnosed as tuberculosis and another was primary lung cancer. Among the 198 cases of primary and metastatic lesions, the discordance rates of ER, PR, HER-2 and Ki-67 were 27.3%, 34.3%, 11.8% and 15.1%, respectively.The expressions of ER, HER-2 and Ki-67 were not significantly different between the primary and metastatic lesions, however, the expressions of PR were more likely to turn negative in the metastases (P<0.001). The disease-free survival (DFS) of patients with ER, PR positive, HER-2 negative and low expression of Ki-67 in metastatic lesion was much longer (P<0.05). Conclusions: The expressions of ER, PR, HER-2 and Ki-67 in metastatic lesions are associated with the prognosis of breast cancer patients.Their expression discordances between primary and metastatic lesions can guide the treatment and evaluate the risks of recurrence and prognosis.


Assuntos
Neoplasias da Mama/metabolismo , Antígeno Ki-67/metabolismo , Recidiva Local de Neoplasia/metabolismo , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Biópsia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Metástase Neoplásica , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Taxa de Sobrevida
15.
Tumour Biol ; 41(9): 1010428319878536, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31552812

RESUMO

Histone H2AX undergoes phosphorylation as an answer to DNA double-strand breaks, which in turn are part of the oncogenic procedure. The detection of gamma-H2AX can potentially serve as a biomarker for transformation of normal tissue to premalignant and consequently to malignant tissues. The aim of this study was to evaluate the clinical significance of gamma-H2AX expression in breast cancer. Gamma-H2AX expression in tissues from 110 breast cancer patients was analyzed by immunohistochemistry and correlated with clinicopathological variables. Greater tumor size, higher grade, and the number of affected lymph nodes are significantly associated with greater values of gamma-H2AX. In addition, gamma-H2AX differs significantly among patients' International Federation of Gynecology and Obstetrics stage. Higher values of estrogen receptor and progesterone receptor are significantly associated with lower gamma-H2AX values. In conclusion, a positive association between gamma-H2AX expression and infaust histopathological parameters was observed.


Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias da Mama Masculina/metabolismo , Neoplasias da Mama/metabolismo , Histonas/biossíntese , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/cirurgia , Neoplasias da Mama Masculina/diagnóstico , Neoplasias da Mama Masculina/cirurgia , Feminino , Humanos , Imuno-Histoquímica , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Fosforilação , Receptores Estrogênicos , Receptores de Progesterona
16.
Pharm Res ; 36(11): 154, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31482205

RESUMO

PURPOSE: Conjugation of nanocarriers with antibodies that bind to specific membrane receptors that are overexpressed in cancer cells enables targeted delivery. In the present study, we developed and synthesised two PAMAM dendrimer-trastuzumab conjugates that carried docetaxel or paclitaxel, specifically targeted to cells which overexpressed HER-2. METHODS: The 1H NMR, 13C NMR, FTIR and RP-HPLC were used to analyse the characteristics of the products and assess their purity. The toxicity of PAMAM-trastuzumab, PAMAM-doc-trastuzumab and PAMAM-ptx-trastuzumab conjugates was determined using MTT assay and compared with free trastuzumab, docetaxel and paclitaxel toward HER-2-positive (SKBR-3) and negative (MCF-7) human breast cancer cell lines. The cellular uptake and internal localisation were studied using flow cytometry and confocal microscopy, respectively. RESULTS: The PAMAM-drug-trastuzumab conjugates in particular showed extremely high toxicity toward the HER-2-positive SKBR-3 cells and very low toxicity towards to HER-2-negative MCF-7 cells. As expected, the HER-2-positive SKBR-3 cell line accumulated trastuzumab from both conjugates rapidly; but surprisingly, although a large amount of PAMAM-ptx-trastuzumab conjugate was observed in the HER-2-negative MCF-7 cells. Confocal microscopy confirmed the intracellular localisation of analysed compounds. The key result of fluorescent imaging was the identification of strong selective binding of the PAMAM-doc-trastuzumab conjugate with HER-2-positive SKBR-3 cells only. CONCLUSIONS: Our results confirm the high selectivity of PAMAM-doc-trastuzumab and PAMAM-ptx-trastuzumab conjugates for HER-2-positive cells, and demonstrate the utility of trastuzumab as a targeting agent. Therefore, the analysed conjugates present an promising approach for the improvement of efficacy of targeted delivery of anticancer drugs such as docetaxel or paclitaxel.


Assuntos
Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Dendrímeros/química , Docetaxel/química , Paclitaxel/química , Receptor ErbB-2/metabolismo , Trastuzumab/química , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/farmacologia , Interações de Medicamentos , Liberação Controlada de Fármacos , Corantes Fluorescentes/química , Humanos , Paclitaxel/farmacologia , Propriedades de Superfície , Trastuzumab/farmacologia , Resultado do Tratamento
17.
Gene ; 721: 144100, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31493508

RESUMO

BACKGROUND: Breast cancer (BRCA) is the most prevalent cancer that threatens female health. A growing body of evidence has demonstrated the non-negligible effects of messenger RNAs (mRNAs) on biological processes involved in cancers; however, there is no definite conclusion regarding the role of mRNAs in predicting the prognosis of BRCA patients. MATERIALS AND METHODS: We systematically screened the mRNA expression landscape and clinical data of samples from the Cancer Genome Atlas (TCGA). Univariate Cox analysis and robust likelihood-based survival analysis were conducted to identify key mRNAs associated with BRCA. Furthermore, risk scores based on multivariate Cox analysis divided the training set into high-risk and low-risk groups. ROC analysis determined the optimal cut-off point for patient classification of risk levels. The prognostic model was additionally validated in the testing set and complete dataset. Finally, we plotted the survival curves for the mRNAs used in our model. RESULTS: We obtained the original expression data of 13,617 mRNAs from a total of 1088 samples. After comprehensive survival analysis, the four-mRNA (ACSL1, OTUD3, PKD1L2, and WISP1) prognosis risk assessment model was constructed. Furthermore, the area under cure (AUC) was 0.834, indicating that the model was meaningful and reasonable. In each dataset, analysis based on the four-mRNA signature risk score indicated that the survival status of the group with high risk score was worse than that of the group with low risk scores. Patients with strong mRNA expression of OTUD3, PKD1L2, and WISP1 tended to have good prognosis, whereas patients with high ACSL1 expression tended to have poor prognosis. CONCLUSION: In summary, we constructed a four-mRNA prognosis risk assessment model for BRCA. The newly developed model offers more possibilities for assessing prognosis and guiding the selection of better treatment strategies for BRCA.


Assuntos
Neoplasias da Mama , Bases de Dados de Ácidos Nucleicos , Modelos Biológicos , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Proteínas de Sinalização Intercelular CCN/biossíntese , Proteínas de Sinalização Intercelular CCN/genética , Coenzima A Ligases/biossíntese , Coenzima A Ligases/genética , Intervalo Livre de Doença , Feminino , Humanos , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/genética , RNA Neoplásico/genética , Receptores Acoplados a Proteínas-G/biossíntese , Receptores Acoplados a Proteínas-G/genética , Taxa de Sobrevida , Proteases Específicas de Ubiquitina/biossíntese , Proteases Específicas de Ubiquitina/genética
20.
Nat Methods ; 16(9): 875-878, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31471617

RESUMO

Single-cell RNA sequencing (scRNA-seq) data are noisy and sparse. Here, we show that transfer learning across datasets remarkably improves data quality. By coupling a deep autoencoder with a Bayesian model, SAVER-X extracts transferable gene-gene relationships across data from different labs, varying conditions and divergent species, to denoise new target datasets.


Assuntos
Neoplasias da Mama/metabolismo , Biologia Computacional/métodos , Leucócitos Mononucleares/metabolismo , Análise de Sequência de RNA/normas , Análise de Célula Única/métodos , Linfócitos T/metabolismo , Transcriptoma , Animais , Teorema de Bayes , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Camundongos , Análise de Sequência de RNA/métodos
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